Antagonism of the Thromboxane‐Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy

Abstract

Background Muscular dystrophy ( MD ) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane‐prostanoid receptor ( TP r) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TP r activation contributes to the cardiac phenotype of MD , and that TP r antagonism would improve cardiac fibrosis and function in preclinical models of MD . Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/ mTR double knockout, and delta‐sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TP r antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban‐treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta‐sarcoglycan knockout mice, respectively. TP r antagonism improved cardiac output in mdx/utrn double knockout and mdx/ mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta‐sarcoglycan knockout mice. Cardiac fibrosis in delta‐sarcoglycan knockout was reduced with TP r antagonism, which also normalized cardiac expression of claudin‐5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TP r antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb‐girdle MD . Based on these studies, ifetroban and other TP r antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD .